Psoriasis is a common, noncontagious, chronic, inflammatory disease with unknown cause. The disease creates worldwide health problems. For example, psoriasis affects nearly 3% of the general population in Faroe Islands and Denmark. Over 7 million people in the United States are afflicted with the disease, which represents a 2% of the population.
The most common symptoms of psoriasis include sharply circumscribed salmon pink patches covered with silvery white scales. Diagnosis is usually made by observation and examination of the skin. Different types of psoriasis exist and range from mild to severe. Psoriasis is variable, and one type can change into another type or several types can coexist at the same time. The National Psoriasis Foundation describes the types of psoriasis as follows:
1. Plaque Psoriasis
The major symptoms include raised, inflamed lesions that are covered in white scale. It is among the most common types, which is also called psoriasis vulgaris. Plaque psoriasis can be found anywhere on skin, more often on scalp, elbows, knees, and trunk of the body.
2. Guttafe Psoriasis
The major symptoms include small, drop-like dots with some scale. Guttafe psoriasis can be found on trunk, legs, and arms of the body.
3. Inverse Psoriasis
The major symptoms include smooth inflamed lesions with no scale. Inverse psoriasis can be found at skin folds, armpit, and groin of the body.
4. Erthrodermic Psoriasis
The major symptoms include severe sloughing of the skin with redness. Erthrodermic psoriasis can be found anywhere on body.
5. Psoriatic Arthritis
The major symptoms include swelling and inflammation of joints, which results from 10% of psoriasis patients. Psoriatic arthritis can be found on knees, hips, elbows, spine, hands, and feet of the body.
6. Scalp Psoriasis
Scalp psoriasis is the usual plaque type. Scalp psoriasis exists in 50% of psoriasis patients.
7. Nail Psoriasis
The major symptoms include pitting, discoloration, and loss of fingernails and toenails. Nail psoriasis is usually shown by inflammation of skin around the nail.
A combination of genetic, environmental, and immunological factors may contribute to psoriasis. It is believed that a person is predisposed to developing psoriasis, however, the pattern of inheritance has not been found. Only one in three patients reports a family history of the disease, whereas others show no incidence of psoriasis in the family. Important triggers have been found that may initiate the development of the disease in those that are predisposed to developing the disease. The triggers may include superantigens such as bacteria, virus, and fungus, vaccinations, intramuscular injection, certain drugs, stress, injury to the skin, and Koebner phenomenon. As a result of the trigger, the immune system of the person predisposed to developing the disease causes excessive skin cell reproduction.
In normal skin growth, skin cells produced in the basal cell layer move up through the epidermis to the outermost layer, the stratum corneum. The process from cell birth to cell death takes about 28–30 days. When skin is damaged, the cycle runs much faster. In psoriasis patients, though there is no wound at the site of psoriatic lesions, skin cells called keratinocyte act in a regenerative manner. New skin cells are produced in 2–4 days, thus making it very difficult to shed old cells at an adequate rate. The elevated scaly lesions are a result of the buildup of cells. The white scale is the dead skin cells, and the redness a result of an increase in blood flow to areas of high cell division. Psoriasis is characterized by extreme epidermal hyper-proliferation, which is an excessive growth associated with incomplete and accelerated differentiation and noticeable inflammation of epidermis and dermis at local sites with development of neutrophil microabscess and enhanced induction of cycling T lymphocytes. The cause of psoriasis was initially thought to involve one of the mediators of hyper-proliferation. However, researchers began to focus on the immune system, after by chance it was discovered that cyclosporine with immunosuppressive effects significantly improved conditions in psoriasis patients. Thus, psoriasis is now viewed as an autoimmune disease.
At the present time, there are three major theories relating to the pathogeneisis, origin, and development of psoriasis. The first theory believes that psoriasis is due to T-lymphocytes activated in psoriatic lesions by cytokines that are released from epidermal keratinocyte. The second theory believes that psoriasis derived from antigen dependent T-cell activation which causes the release of cytokines that activate epidermal keratinocyte. The third theory believes that psoriasis is caused by autoimmune reactions of CD8+ “killer” T-lymphocytes with epidermal keratinocyte trigger epidermal activation.
Psoriasis does not affect overall health and is not life threatening, but people do die from complications associated with the disease. The physical and emotional effects of psoriasis can be painful. Psoriasis causes disfigurements which physically limit, thus affect job performance and leisure activities, and cause frustration, embarrassment, fear, and depression for psoriasis sufferers, especially the ones with severe types. Psoriasis is persistent and unpredictable in its course. So far, no single treatment has been found that works for every patient. As a result, a variety of treatments have been developed which can be used alone or in combination to treat the disease. These treatments may diminish symptoms transiently but they are not curative. Very often they are aesthetically unpleasant, expensive, time-consuming, and with side effects. The present treatment is usually disappointing and unsatisfactory.
Mild forms of psoriasis are treated by topical applications of glucocorticoid such as Corticaine. Keratolytic agents, such as sulfur or salicylic acid, are useful adjuvants. Side-effects are mild. Moderate forms of psoriasis are usually treated with anthralin/dithranol or tar preparations such as Pentrax. Side-effects are mild to moderate. Severe cases of psoriasis or mild to moderate forms that do not respond to the conventional therapy may require treatment with systemic medication. Side-effects are usually severe.
Current therapies for psoriasis are as follows:
1. Phototherapy:
a). Narrow band ultraviolet B phototherapy (UVB) has been used; the side effects include burning and carcinogenesis.
b). Psoralen with ultraviolet A (PUVA) has been used; there are long term problem of carcinogenesis and short term problems of nausea, phototoxicity, and pruritus.
c). Photodynamic therapy has been used; the limitations include photosensitivity and tissue destruction.
2. Drugs approved for other uses:
a). Zidovudine (Retrovir), which is also the drug used to slow AIDS. Side effects involve a decrease in RBC and WBC counts.
b). Histamine2 Receptor Antagonists has been used for treating psoriasis; the drug is also used to treat stomach ulcers, for example, ranitidine (Zantac) and cimetidine (Tagament) are also used for treating psoriasis. Side effects involve an initially worsening of symptoms.
c). Antithyroid Thioureylenes is used; the drug is also used for hyperthyroidism. An example is propylthiouracil and methimazole (Tapazole). Side-effects include hypothyroidism, but the side effect is reduced with a topical formulation.
d). Capsaicin (Zostrix 0.025% cream) is approved for pain relief in rheumatoid arthritis, osteoarthdtis, and neuralgia. The major side effect is stinging.
3. New drugs developed for psoriasis:
a). Acitretin (Neotegison/Neotigason) is a second-generation monoaromatic retinoid. This drug is teratogenic. Related retinoid Etretinate (Tegison/Tigason) shows similar effects.
b). Fumaric acid therapy is used. The side effects include abdominal disturbances, lymphopenia, flushing, and mild change of hepatic and renal function. In 85% of patients, long term therapy causes lymphopenia.
c). Vitamin D derivatives are used. 1,25 dihydroxyvitamin D3 (1,25-(OH)2D3) shows hypercalciuria in systemic and topical applications. A synthetic 1,24-dihydroxyvitamin D3 analogue, Calcipotriene, in the form of ointment (Dovonex ointment), diminishes hypercalciuria side-effects but results in face and intertriginous irritation. Tacalcitol also shows face irritation.
d). Tazarotene (Tazorac) is an acetylenic retinoid molecule. Topical application showed dose-related irritation.
4. Immune therapy:
a). Cyclosporine (Sandimmune) is approved for use in organ transplantation. Some side effects are potentially toxic which include headaches, gastrointestinal disturbances, hypertrichosis, paresthesias, and gingival hyperplasia. It is extremely important that nephrotoxicity be carefully monitored with this drug. Side-effects increase with length of time the drug is administered, so it is not an acceptable long-term therapy for patients. A new formulation called Neoral (approved for organ transplantation) may reduce toxicity, but further studies are needed.
b). DAB3891L-2 is a cytotoxin that selectively attacks IL-2 receptors on cells and destroys them. Side effects include: flu-like symptoms, pruritus, and transient transaminase elevation.
c). Tacrolimus (Prolaf) is a macrolide antibiotic used to treat allograft rejection in liver transplant patients. Side-effects are similar to Cyclosporine.
d). CTLA41g is an experimental agent that blocks the second signal in T-cell activation. Side-effects are unknown. Clinical trials are in progress.
e). Anti-CD4 Monoclonal Antibody shows side effects include chills and fever. More in depth toxicity studies are needed.
f). T-cell receptor peptide vaccines include Vβ3 and Vβ13.1. T-cells are targeted. Clinical trials are in progress to determine toxicity of the therapy.
g). Other immunologic agents may include TNF-alpha inhibitors and antisense oligonucleotides. Side-effects are unknown.
Monoclonal antibody (mAb) preparations may be effective in fighting malignancy, infection, and immune disorders. A monoclonal antibody is directed against and binds to a single epitope on an antigenic molecule. Characteristics such as homogeneous high binding affinity and specificity make them suitable for developing therapeutics. For example, murine antibodies have been used in diagnosis of human disease, such as leukemias, lymphomas, solid tumors (e.g., colon, breast, hepatic), AIDS and autoimmune diseases. Alternatively, mouse/human chimeric antibodies have been created, and shown to exhibit the binding characteristics of the parental mouse antibody, and effective functions associated with the human constant region. U.S. Pat. Nos. 4,816,567, 4,978,745, 4,975,369, 4,816,397, 5,750,105, and 6,024,956, which are herein incorporated by reference. Generally, the first step for chimeric antibody preparation is isolation of DNA fragments encoding variable heavy and light chains from pre-existing murine hybridoma or spleen cells of immunized mouse. The cloned variable region genes are then ligated into an expression vector containing cloned cassettes of the appropriate heavy or light chain human constant region gene. The chimeric genes are then expressed in a cell line of choice, usually a murine myeloma line.
However, mAb preparations, either as murine monoclonal antibodies or chimeric antibodies, for the most part, have been administered using systemic drug delivery methods, i.e., for internal use. There is hardly any report on the use of mAb in topical treatment.
Topical treatments are preferred for treating psoriasis and other skin inflammatory diseases because there are less side-effects. A concerted effort to develop a topical preparation containing antibodies for treating psoriasis has not been undertaken. This is because it has been accepted that a sufficient level of antibodies cannot be absorbed through the skin to combat psoriasis. It is unknown exactly which biological factors play a role in the manifestation of the disease. This has made it difficult to develop a topical treatment. With a topical treatment, lower levels of antibodies reach the target site. A topical treatment therefore requires the use of an antibody or other active ingredients which neutralize a biological factor which is directly linked to the manifestation of the disease.
The present invention provides an effective topical treatment for skin inflammatory diseases including psoriasis, based on the fact that interleukin-8 (IL-8) or neutrophil-activating protein (NAP-1) has been found to play a significant role in the manifestation of psoriasis and other inflammatory skin conditions. It is not previously known that antibodies or other agents that neutralize IL-8 are effective in the treatment of psoriasis and other inflammatory skin diseases. Particularly, the present invention reveals that the interleukin-8 (IL-8) level is only locally elevated in inflammatory tissues but not in the circulation of the entire body. Expression of high levels of IL-8 in psoriatic tissues contributes to the local inflammation. The topical treatment of cream preparation of present invention has many advantages over systemic administration of anti-IL-8 antibodies. It does not generally affect the levels and expression of IL-8 in the body. Because IL-8 is known to be an important cytokine with multiple physiological functions, total elimination of IL-8 by prolonged treatment of high dose neutralizing antibody in the circulation may cause immune system disturbance and severe side-effects in long term.
The present invention meets the need for a pharmaceutical formulation for topical treatment of psoriasis that is effective in neutralizing biological factors that are directly involved in the manifestation of the disease, and specifically, the need for a topical treatment for psoriasis that contains antibodies for neutralizing IL-8.
The present invention meets the need for a pharmaceutical formulation for protection of antibody activities, and the formulations can keep and maintain the neutralizing activity of antibody for at least two years. The cream formulation of present invention can also facilitate antibodies to penetrate into psoriatic lesions in quantities sufficient to reach therapeutic levels.
The treatment method of the present invention shows advantages over prior treatment methods in the following: (1) the topical application as disclosed in the present invention minimizes the toxic side effects that are often associated with systemic drug delivery, because the treatment is applied locally; (2) the antibodies used in the topical treatment are unique in that they are specific, homogeneous, and can be produced in vitro at infinitum; and (3) the antibodies to IL-8 specifically neutralize IL-8 in psoriatic lesions, but not anything else; and (4) the topical treatment method as disclosed in the present invention does not induce a HAMA reaction that are often associated with systemic delivery of murine antibody, chimeric antibody and humanized antibody.